Urea: Metabolism product of protein breakdown

Urea is a metabolic product of amino acid breakdown. Urea-related indicators also help assess the functioning of the kidneys. Changes in urea are represented by the BUN index. The amount of urea in the body can increase or decrease due to many different reasons. Here, let's find out with SignsSymptomsList about urea and its metabolism; as well as health conditions related to BUN (an indicator of blood urea concentration).

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• 1. What is urea?
• 2. Urea discovery history
• 3. Urea production and excretion
• 4. Urea cycle
• 5. Blood urea concentration

1. What is urea?

Urea (also known as carbamide) is a waste product of many living organisms. It is the main organic component of human urine. That's because it's at the end of a chain reaction that breaks down the amino acids that make up proteins.

These amino acids are metabolized in the liver into: ammonia, CO2, water and energy. But ammonia is toxic to cells. Therefore, it must be eliminated from the body. Aquatic organisms, such as fish, can release ammonia directly into the water. But terrestrial animals need a different method of disposal. So the liver converts ammonia into a non-toxic compound – urea. It is safely transported in the blood to the kidneys; where it is eliminated in the urine.

Any condition that interferes with the kidneys' elimination of urea can lead to urotoxicity, a buildup of urea and other nitrogenous waste products in the blood that can be fatal. To reverse the condition, the cause of the kidney failure must be removed, or the patient must undergo dialysis to remove waste products from the blood.

Urea is a small organic molecule (M = 60) consisting of two amine groups (-NH2) and one carbamyl group (CO) linked together.

2. Urea discovery history

Urea has a rather interesting history. It was first discovered and isolated from human urine by HM Rouelle in 1773. It was then successfully synthesized by Friedrich Wohler in 1828. The synthesis was almost a coincidence. Because Wohler was trying to create another compound, ammonium cyanate, to continue the cyanate research he had been working on for several years before. When he added silver cyanate to ammonium chloride solution, he obtained a white crystalline substance, which proved to be similar to urea obtained from urine.

This discovery is important, as it makes urea the first organic compound to be synthesized from completely inorganic starting materials.

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3. Urea production and excretion

Urea production is related to the proteins we eat. Proteins are composed of chains of amino acids. Amino acids are separated from each other as proteins from food are digested in the gastrointestinal tract. They are then absorbed through the lining of the digestive tract and used to build specific proteins needed by our bodies.

Excess amino acids are broken down in a process known as deamination. In this process, the amine group of an amino acid (-NH2) is removed and converted into a molecule of ammonia (NH3). Detoxification takes place mainly in the liver.

Ammonia is very toxic to cells. Ammonia molecules react with carbon dioxide in the body to produce urea, a much safer chemical. The conversion of ammonia to urea takes place in the liver by a process known as the urea cycle. Blood vessels transport urea to the kidneys to remove it from the blood and into the urine. Urine is stored in the bladder and released into the environment when we urinate. The overall process is called excretion. Small amounts of urea are eliminated from our body in sweat.

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4. Urea cycle

The urea cycle removes ammonia from the blood and produces urea. Finally excreted in the form of urine. This cycle is carried out by the cells of the liver, and as the name suggests indicates the last step of metabolism to the previous step of the cycle.

4.1. Summary of steps in the urea cycle

Ammonia is formed by the breakdown of amino acids/gut bacteria.

• Mitochondrial stage:

Carbamoyl phosphate is formed from ammonia and bicarbonate, by CPSI.

OTC condenses carbamoyl phosphate and ornithine to form citrulline.

Citrulline is then transported by SLC25A15 to the cytoplasm.

• Cell stage:

– ASS condenses citrulline and aspartate to form argininenosuccinate.

Argininosuccinate is broken down by ASL to arginine and fumarate.

– Next, Arginine is broken down by arginase into urea and ornithine.

Ornithine translocase transports ornithine into mitochondria.

There, it is again used by the OTC, to form citrulline. The citrulline is then processed to form urea and ornithine again, and the cycle continues. During the cycle, urea is the only new product formed, while all other molecules used in the cycle are recycled.

4.2. What happens when the urea cycle goes wrong?

If there is a problem with the urea cycle, the blood ammonia levels will rise, causing uremia. Ammonia can cross the barrier between the blood stream and the brain.

Once it enters the brain, it can stop the TCA cycle by depleting one of the metabolites, α-ketoglutarate. This means that these brain cells cannot produce energy. It will eventually lead to serious neurological problems such as irreversible brain damage.

The cause of the deviation can be due to:

• Liver damage ( cirrhosis ).
• Genetic defect of one of the above enzymes.

In both cases, elevated ammonia levels come with potential consequences.

Inherited urea cycle defects are part of a “metabolic defect”. This is called a “urea cycle disorder”. Symptoms usually appear in newborns about 24-48 hours after birth. The most severe symptoms are seen in infants with defects in CPS.

5. Blood urea concentration

The BUN test (or blood urea nitrogen test) helps detect blood urea levels. If the kidneys do not do a good job of removing this substance from the body, the amount of urea in the blood will increase. The BUN test can show how well the kidneys are working.

The results of the blood urea nitrogen test are measured in milligrams per deciliter (mg/dL) in the United States and millimoles per liter (mmol/L) internationally. In general, about 7 to 20 mg/dL (2.5 to 7.1 mmol/L) is considered normal.

But the normal range can vary, depending on the reference range the lab uses and your age. You should ask your doctor to explain the results to you.

Urea nitrogen concentrations tend to increase with age. Newborns have lower levels than others and ranges in children also vary. In general, a high blood urea nitrogen level means your kidneys are not working well.

5.1. An increase in the concentration of urea in the blood

There are many causes of high blood urea levels, including:

• Urinary tract obstruction.
• Decreased renal perfusion due to: Congestive heart failure or recent heart attack.
• Hypovolemic shock.
• Severe hypotension.
• Stomach bleeding.
• Severe burns.
• Certain medications, such as some antibiotics.
• Eating a lot of protein-rich foods causes the liver to produce large amounts of urea.

Kidney disease can lead to increased urea in the blood.

• Dehydration due to: low fluid intake; excessive dehydration (sweating, vomiting, diarrhea, diuretics, etc.). Dehydration will also increase blood urea levels. As this depends on the amount of water in the blood. If there is less water than usual in the blood but the same amount of urea, the urea concentration will be higher than normal.
• Aging.
• Injury.
• Severe infection.

Some treatments for high blood urea nitrogen:

• Eliminate protein from the diet.
• Remove excess ammonia.
• Replenish the missing urea cycle molecules.
• In addition, sodium benzoate and sodium acetate can be used to form ammonia-containing compounds that can be excreted in the feces.
• The sugar lactulose has been shown to reduce the production of ammonia by intestinal bacteria, as well as promote the excretion of ammonia in the stool.
• Alternatively, antibiotics can be used to eliminate ammonia-forming intestinal bacteria.

5.2. Decrease in blood urea concentration

There may also be lower-than-normal blood urea levels. This could be due to:

• Pregnancy.
• Advanced liver disease (cirrhosis, liver failure ).
• Inherited defect in the “urea cycle” (decreased urea synthesis).
• Drinking too much water and thinning the blood.
• Not eating a lot of protein or not being able to absorb enough amino acids through the wall of the small intestine due to health problems.
• One health problem that can produce low urea levels is celiac disease. Villi are villi on the lining of the small intestine where digested food is absorbed. In celiac disease , the consumption of gluten damages the villi. This greatly reduces the absorption of nutrients, including protein. Gluten is a complex of proteins found in several grains, including wheat, rye, and barley. While most people eat gluten with no problem, some people are gluten intolerant.

Urea is a metabolic waste product that is excreted in the urine by the kidneys. Kidney disease is associated with decreased urea excretion and consequent increased blood levels. The limitation of urea in renal function testing is related to decreased sensitivity and specificity, so that normal urea does not necessarily rule out nephropathy and mild to moderate elevation in urea cannot be attributed to kidney disease.

Doctor Truong My Linh